Chain flexibility and configurational dimensions of left handed Z- DNA and right handed B-DNA helices

The configurational behaviour of flexible helices of right handed B- and left handed Z-types have been analysed using statistical mechanical procedures. The configuration-dependent parameter, most importantly, the persistence length has been computed, using the heminucleotide scheme of treating polynucleotide chains under the approximation that perturbations in the backbone torsions produce sufficient flexibility in these helices. The values of persistence lengths obtained for Z-helices are very much higher than that of B-helices indicating that former is less flexible compared to the latter. These are in accordance with the results obtained recently on B- and Z-forms of poly(dG-dC) · (dG-dC) using light scattering studies. Also the persistence lengths of BII-DNA helices characterised by a skew 3'-hemiucleotide (ε ≃ 270°), and also when they coexist with B-DNA have been computed and the values lie within the range of experimentally reported values on B-helices. It is argued that the decrease in the persistence length values of B-DNA at higher salt concentration is due to additional small fluctuations in sugar residue torsions induced due to neutralisation of electrostatic repulsions between adjacent phosphates of the nucleotide. Noteworthy is that these are correlated to winding angle variations and the consequent bending of the helix

New insights into DNA triplexes: residual twist and radial difference as measures of base triplet non-isomorphism and their implication to sequence-dependent non-uniform DNA triplex

DNA triplexes are formed by both isomorphic (structurally alike) and non-isomorphic (structurally dissimilar) base triplets. It is espoused here that (i) the base triplet non-isomorphism may be articulated in structural terms by a residual twist (Δt°), the angle formed by line joining the C1′…C1′ atoms of the adjacent Hoogsteen or reverse Hoogsteen (RH) base pairs and the difference in base triplet radius (Δr Å), and (ii) their influence on DNA triplex is largely mechanistic, leading to the prediction of a high (t + Δt)° and low (t − Δt)° twist at the successive steps of Hoogsteen or RH duplex of a parallel or antiparallel triplex. Efficacy of this concept is corroborated by molecular dynamics (MD) simulation of an antiparallel DNA triplex comprising alternating non-isomorphic G*GC and T*AT triplets. Conformational changes necessitated by base triplet non-isomorphism are found to induce an alternating (i) high anti and anti glycosyl and (ii) BII and an unusual BIII conformation resulting in a zigzag backbone for the RH strand. Thus, base triplet non-isomorphism causes DNA triplexes into exhibiting sequence-dependent non-uniform conformation. Such structural variations may be relevant in deciphering the specificity of interaction with DNA triplex binding proteins. Seemingly then, residual twist (Δt°) and radial difference (Δr Å) suffice as indices to define and monitor the effect of base triplet non-isomorphism in nucleic acid triplexes

Incidence of types of hypospadias in and around Tumkur district, Karnataka, India: an anatomical classification

Background: Hypospadias is the second most common congenital anomaly in children. It is characterized by the abnormal ventral opening of the urethral meatus. Abnormal urethral opening may be located on the penile shaft, scrotum or perineum respectively. This article mainly deals with the embryology, etiology, anatomy and incidence of different types of hypospadias in Tumakuru rural district.Methods: This study was interdepartmental and prospective, consisting of 80 cases conducted at department of pediatric surgery and Anatomy and the period of study was from April 2013 to March 2017. The hypospadias have been classified into 1) Proximal hypospadias 2) Midshaft hypospadias, 3) Distal Hypospadias according to the location of external urethral opening.Results: Out of the 80 cases, distal hypospadias is the most common incidence followed by midshaft and proximal hypospadias.Conclusions: The condition is repairable in the vast majority of cases, leaving a functional and normal looking penis. Early diagnosis and surgical intervention, hypospadias and chordee repair procedures are highly successful and can avoid the emotional distress

Visualisation of inter loop tertiary base pairing and stacking interactions in an unusual slipped loop DNA structure

The conformation of an unusual slipped loop DNA structure exhibited by the sequence d(GAATTCCCGAATTC)2 is determined using a combination of geometrical and molecular mechanics methods. This sequence is known to form a B-DNA-like duplex with the central non-complementary cytosines extruded into single stranded loop regions. The unusual feature is that the interior guanine does not pair with the cytosine across, instead, it pairs with the cytosine upstream by skipping two cytosines, leading to a slipped loop DNA structure with the loops staggered by two base pairs. The two loops, despite being very small, can fold across minor or major groove symmetrically or asymmetrically disposed, with one of the loop bases partially blocking the major or minor groove. Most interestingly, for certain conformations, the loop bases approach one another at close proximity so as to engage even in base pairing as well as base stacking interactions across the major groove. While such pairing and stacking are common in the tertiary folds of RNA, this is the first time that such an interaction is visualized in a DNA. This observation demonstrates that a W-C pair can readily be accomplished in a typical slipped loop structure postulated for DNA. Such tertiary loop interaction may prevent access to regulatory proteins across the major groove of the duplex DNA, thus providing a structure-function relation for the occurrence of slipped loop structure in DNA

Co-Crystal Structures of PKG Iβ (92–227) with cGMP and cAMP Reveal the Molecular Details of Cyclic-Nucleotide Binding

Cyclic GMP-dependent protein kinases (PKGs) are central mediators of the NO-cGMP signaling pathway and phosphorylate downstream substrates that are crucial for regulating smooth muscle tone, platelet activation, nociception and memory formation. As one of the main receptors for cGMP, PKGs mediate most of the effects of cGMP elevating drugs, such as nitric oxide-releasing agents and phosphodiesterase inhibitors which are used for the treatment of angina pectoris and erectile dysfunction, respectively. configuration, with a conserved threonine residue anchoring both cyclic phosphate and guanine moieties. The structure of CNBD-A in the absence of bound cyclic nucleotide was similar to that of the cyclic nucleotide bound structures. Surprisingly, isothermal titration calorimetry experiments demonstrated that CNBD-A binds both cGMP and cAMP with a relatively high affinity, showing an approximately two-fold preference for cGMP. conformation through its interaction with Thr193 and an unusual cis-peptide forming residues Leu172 and Cys173. Although these studies provide the first structural insights into cyclic nucleotide binding to PKG, our ITC results show only a two-fold preference for cGMP, indicating that other domains are required for the previously reported cyclic nucleotide selectivity

Tertiary structure of tRNAPhe. A possible correlation between the structural functional unit of this tRNA and its exonic sequence.

It has been shown recently [Go (1981) Nature (London) 291, 90-92; Blake (1983) Trends Biochem Sci. 8, 11-13] that the exonic regions of the genes of proteins haemoglobin, lysozyme and immunoglobin correspond closely to the compactly folded structural units. Despite the absence of classical domain structures in tRNA compared with those found in several proteins, close inspection of certain features in the distance maps obtained for yeast tRNAPhe using the conformationally equivalent heminucleotide scheme reveals that a similar situation might also be present in ribonucleic acids such as tRNA species and the exonic sequences of their genes. Also it seems possible that certain segments of yeast tRNAPhe may be characterized as possessing a domain-like character, and this seems to provide stereochemical support for possible conservation of L-shape structure for tRNA species lacking the entire dihydrouridine arm such as those found in mitochondria

Analysis of the possible helical structures of nucleic acids and polynucleotides. Application of (n-h) plots.

The two helical parameters n and h where n is the number of nucleotide residues per turn and h is the height per nucleotide residue have been evaluated for single stranded helical polynucleotide chains comprising C(3') -endo and C(2') endo class of nucleotides. The helical parameters are found to be especially sensitive to the C(4')-C(3') (sugar pucker) and the C(4')-C(5') torsions. The (n-h) plots display only one important helix forming domain for each class of nucleotides characterized by the sugar pucker and the C(4')-C(5') torsion. A correlation between the (n-h) plots and the known RNA (A,A') and DNA (A,B,C) helical forms has been established. It is found that all forms of helices except the C-DNA possess a favorable combination of P-O torsions. The analysis of the (n-h) plots suggests that C-DNA can have a conformation very similar to B-DNA. Although the (n-h) plots predict the stereochemical possibility of both right-handed and left-handed helices, nucleic acids apparently prefer right-handed conformation because of the energetics associated with the sugar-phosphate backbone and the base